CD8 positive cytotoxic T lymphocytes (CTLs) have been shown to recognize epitope peptides derived from the tumor-associated antigens (TAAs) found on the major histocompatibility complex (MHC) class I molecule, and then kill the tumor cells. Since the discovery of the melanoma antigen (MAGE) family as the first example of TAAs, many other TAAs have been discovered, primarily through immunological approaches (NPL 1, 2). Some of these TAAs are currently undergoing clinical development as immunotherapeutic targets.
TAAs which are indispensable for proliferation and survival of cancer cells are valiant as targets for immunotherapy, because the use of such TAAs may minimize the well-described risk of immune escape of cancer cells attributable to deletion, mutation, or down-regulation of TAAs as a consequence of therapeutically driven immune selection. Accordingly, the identification of new TAAs capable of inducing potent and specific anti-tumor immune responses warrants further development. Thus, the clinical application of peptide vaccination strategies for various types of cancer is ongoing (NPL 3-10). To date, there have been several reports of clinical trials using these tumor-associated antigen derived peptides. Unfortunately, so far, these cancer vaccine trials have yielded only a low objective response rate has been observed in these cancer vaccine trials so far (NPL 11-13). Accordingly, there remains a need in the art for new TAAs suitable for use as immunotherapeutic targets.
The CDCA1 gene, also known as cell division cycle associated 1, has been identified as a member of a class of genes that are coexpressed with cell cycle genes, such as CDC2, cyclin, topoisomerase II and the others (NPL 14). CDCA1 in particular was found to be associated with centromeres of mitotic HeLa cells and was therefore considered a functional homologue of yeast Nuf2 (NPL 15).
In addition, through gene expression profile analysis using a genome-wide cDNA microarray containing 23,040 genes (NPL 16), CDCA1 has also been identified as a novel molecule up-regulated in breast cancer (PTL 1), bladder cancer (PTL 2), esophageal cancer (PTL 3), small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) (PTL 4), the contents of such disclosure being incorporated by reference herein. Expression of CDCA1 was found to be particularly up-regulated in SCLC, NSCLC and tumor cell lines, though no expression was detected except testis among 23 normal tissues. Furthermore, down-regulation of CDCA1 expression by siRNA has been shown to cause cell growth suppression in CDCA1 expressing lung cancer cell lines (PTL 4).
Taken together, these data suggest that CDCA1 is a novel, potentially universal oncoantigen. Accordingly, epitope peptides derived from CDCA1 may be applicable as cancer immunotherapeutics for the treatment of a wide array of cancers.
Recently, highly immunogenic CDCA1-derived cytotoxic T lymphocytes (CTL)-epitopes that can induce tumor-reactive and HLA-A2 (A*02:01)-restricted CTL from PBMCs of lung cancer patients (NPL 17, PTL 6) have been identified. Furthermore, CDCA1-derived HLA-A24-restricted CTL-epitopes have been also identified (PTL 7). Therefore, CDCA1 remains an attractive target molecule applicable to cancer immunotherapy.
Tumor-specific CD4+ helper T (Th) cells, especially T-helper type 1 (Th1) cells play a critical role in efficient induction of CTL-mediated antitumor immunity (NPL 18). The IFN-gamma primarily produced by Th1 cells is critical for induction and maintenance of long lived CTL responses, providing help through multiple interactions which are critical in the preservation of immunological memory (NPL 19, 20). The IFN-gamma secreted by Th1 cells also mediates direct antitumor or anti-angiogenic effect (NPL 21). Furthermore, it has been shown that Th cells must pave the way for entry of CTLs at tumor site (NPL 22). Therefore, identification of tumor-associated antigen (TAA)-derived Th cell epitopes that can activate specific Th1 cell is important for induction of an effective tumor immunity in tumor-bearing hosts; ideally, the design of effective vaccines should include multiple epitopes to stimulate both CTL and Th1 cells (NPL 23). However, no such epitope derived from CDCA1 has yet been identified.